A CD25-biased interleukin-2 for autoimmune therapy engineered via a semi-synthetic organism.

Autor: Ptacin JL; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Ma L; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Caffaro CE; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Acuff NV; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Germar K; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., Severy P; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., Qu Y; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., Vela JL; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., Cai X; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., San Jose KM; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Aerni HR; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Chen DB; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Esche E; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Ismaili TK; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Herman R; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Pavlova Y; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Pena MJ; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Nguyen J; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Koriazova LK; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Shawver LK; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Joseph IB; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Mooney J; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA., Peakman M; Sanofi, 350 Water St., Cambridge, MA, 02141, USA., Milla ME; Synthorx, a Sanofi Company, 11099 N. Torrey Pines Rd. Suite 190, La Jolla, CA, 92037, USA. marcos@samsaracap.com.
Jazyk: angličtina
Zdroj: Communications medicine [Commun Med (Lond)] 2024 Mar 26; Vol. 4 (1), pp. 58. Date of Electronic Publication: 2024 Mar 26.
DOI: 10.1038/s43856-024-00485-z
Abstrakt: Background: Natural cytokines are poorly suited as therapeutics for systemic administration due to suboptimal pharmacological and pharmacokinetic (PK) properties. Recombinant human interleukin-2 (rhIL-2) has shown promise for treatment of autoimmune (AI) disorders yet exhibits short systemic half-life and opposing immune responses that negate an appropriate therapeutic index.
Methods: A semi-synthetic microbial technology platform was used to engineer a site-specifically pegylated form of rhIL-2 with enhanced PK, specificity for induction of immune-suppressive regulatory CD4 + T cells (Tregs), and reduced stimulation of off-target effector T and NK cells. A library of rhIL-2 molecules was constructed with single site-specific, biorthogonal chemistry-compatible non-canonical amino acids installed near the interface where IL-2 engages its cognate receptor βγ (IL-2Rβγ) signaling complex. Biorthogonal site-specific pegylation and functional screening identified variants that retained engagement of the IL-2Rα chain with attenuated potency at the IL-2Rβγ complex.
Results: Phenotypic screening in mouse identifies SAR444336 (SAR'336; formerly known as THOR-809), rhIL-2 pegylated at H16, as a potential development candidate that specifically expands peripheral CD4+ Tregs with upregulation of markers that correlate with their suppressive function including FoxP3, ICOS and Helios, yet minimally expands CD8 + T or NK cells. In non-human primate, administration of SAR'336 also induces dose-dependent expansion of Tregs and upregulated suppressive markers without significant expansion of CD8 + T or NK cells. SAR'336 administration reduces inflammation in a delayed-type hypersensitivity mouse model, potently suppressing CD4+ and CD8 + T cell proliferation.
Conclusion: SAR'336 is a specific Treg activator, supporting its further development for the treatment of AI diseases.
(© 2024. The Author(s).)
Databáze: MEDLINE
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